Peptides represent valuable tools for investigating biological systems, studying the binding and activity properties of biomolecules (e.g., enzymes, cell receptors, antibodies, kinases), and for validating pharmacological targets. Peptide-based molecules have also attracted increasing attention as therapeutic agents, in particular in the context of challenging drug targets such protein-protein and protein-nucleic acids interactions. While many peptides exhibit interesting biological activity, linear peptides do not generally represent suitable pharmacological agents due to poor proteolytic and metabolic stability, limited cell permeability, and promiscuous binding as a result of conformational flexibility. The use of molecular constraints to restrict the conformational freedom of the molecule backbone can be used to overcome these limitations. In many cases, conformationally constrained peptides exhibit enhanced enzymatic stability (Fairlie, Tyndall et al. 2000; Wang, Liao et al. 2005), membrane permeability (Walensky, Kung et al. 2004; Rezai, Bock et al. 2006; Rezai, Yu et al. 2006), and protein binding affinity (Tang, Yuan et al. 1999; Dias, Fasan et al. 2006) and selectivity (Henchey, Porter et al. 2010), compared to their linear counterparts. Constraints that lock-in the active conformation of a peptide molecule can result in increased affinity due to the reduced conformational entropy loss upon binding to the receptor. Macrocyclic peptides have thus emerged as promising molecular scaffolds for the development of bioactive compounds and therapeutic agents (Katsara, Tselios et al. 2006; Driggers, Hale et al. 2008; Obrecht, Robinson et al. 2009; Marsault and Peterson 2011).
Reflecting its abundance in protein structures, α-helices are often encountered at the interface of protein-protein and protein-nucleic acids complexes (Jochim and Arora 2009). Once excised from the protein context, linear peptides encompassing these secondary structural motifs rarely adopt a stable α-helical conformation in solution. Accordingly, a number of strategies have been developed for stabilization and mimicry of α-helical peptides (Henchey, Jochim et al. 2008) as a means to generate bioactive molecules that can target and modulate these biomolecular interactions. A common approach in this area has involved the use of covalent inter-side-chain linkages such as disulfide bonds (Jackson, King et al. 1991), lactam (Osapay and Taylor 1992), thioether (Brunel and Dawson 2005) or triazole (Scrima, Le Chevalier-Isaad et al. 2010; Kawamoto, Coleska et al. 2012) bridges, ‘hydrocarbon staples’ (Blackwell and Grubbs 1998; Schafmeister, Po et al. 2000; Bernal, Wade et al. 2010), and cysteine cross-linking moieties (Zhang, Sadovski et al. 2007; Muppidi, Wang et al. 2011; Jo, Meinhardt et al. 2012; Spokoyny, Zou et al. 2013). Another approach has entailed the stabilization of α-helical peptides via the introduction of so-called ‘hydrogen bond surrogates’, i.e. hydrocarbon linkages replacing an N-terminal i/i+4 hydrogen bond (Wang, Liao et al. 2005).
Citation or identification of any reference in Section 2, or in any other section of this application, shall not be considered an admission that such reference is available as prior art to the present invention.